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Study of tissue-specific dihydrodiol dehydrogenase

Research Project

Project/Area Number 11672175
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeSingle-year Grants
Section一般
Research Field Biological pharmacy
Research InstitutionGifu Pharmaceutical University

Principal Investigator

HARA Akira  Department of pharmaceutical science Gifu Pharmaceutical University Professor, 薬学部, 教授 (00094334)

Project Period (FY) 1999 – 2000
Project Status Completed (Fiscal Year 2000)
Budget Amount *help
¥3,600,000 (Direct Cost: ¥3,600,000)
Fiscal Year 2000: ¥900,000 (Direct Cost: ¥900,000)
Fiscal Year 1999: ¥2,700,000 (Direct Cost: ¥2,700,000)
Keywordsdihydrodiol dehydrogenase / D-xylose dehydrogenase / new protein family / structure-function relationship / site-directed mutagenesis / anti-inflammatory drug / gene structure / 新規蛋白質ファミリー
Research Abstract

Dihydrodiol dehydrogenase (DD, EC 1.3.1.20), which catalyzes the NADP-dependent oxidation of trans-dihydrodiols of aromatic hydrocarbons, has been shown to be involved in cytotoxicity of the aromatic hydrocarbons. The enzyme exits in multiple forms in mammalian tissues. Of the multiple forms dimeric DD is tissue-specifically expressed, but its structure and physiological function have not been elucidated. This study was performed to elucidate the structure of dimeric DD, its relationship to the function and possible clinical significance. The results obtained are summarized.
1. Dimeric DD in monkey kidney, pig and dog liver was demonstrated to be identical with NADP-dependent D-xylose dehydrogenase (EC 1.1.1.179).
2. The protein sequencing and/or cDNA cloning primary structures of dimeric DDs in rabbit lens, human intestine and the above animal tissues revealed that the enzymes constitute a new protein family with prokaryotic proteins including glucose-fructose oxidoreductase.
3. The site … More -directed mutagenesis on the monkey dimeric DD suggested that Tyr-180 is a catalytic residue, Lys-97 and His-79 function both coenzyme binding and chemical steps of the reaction, and Tyr-71 and His-76 are involved in coenzyme binding. In addition, Trp-125, Asp-176 and Trp-254 were suggested to be responsible for substrate binding, and of the three residues Asp-176 is thought to be important for the adaptation of the alcohol substrate in to the binding site. The crystallographic study is now in progress.
4. Dimeric DD was inhibited by several drugs such as nonsteroidal anti-inflammatory agents, of which the potent inhibitors commonly had 4-hydroxyphenylketone structure. The enzyme's mRNA, although it did not detected in normal human kidney, was detected in one of five renal cancer specimen. The variant gene with respect to exon 4 region was not detected, and such a study for other exon regions will be continued to find clinical significance.
5. During the course of cloning of the genomic gene for dimeric, I noticed that the gene is included in a working draft sequence of chromosome 19. The 5'-noncoding region of this gene contains various putative binding sites for transcription factors.
6. The structural and functional aspects obtained in this study was presented in 10^<th> International Symposium on Enzymology and Molecular Biology of Carbonyl Metabolism (New Mixico, U.S.A., July, 2000). Less

Report

(3 results)
  • 2000 Annual Research Report   Final Research Report Summary
  • 1999 Annual Research Report
  • Research Products

    (9 results)

All Other

All Publications (9 results)

  • [Publications] E.Arimitsu et al.: "Cloning and sequencing of the cDNA species for mammalian dihydrodiol dehydrogenases"Biochem.J.. 342・3. 721-728 (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Y.Asada et al.: "Roles of His-79 and Tyr-180 of D-xylose/dehydrodiol dehydrogenase in catalytic function"Biochem.Biophys.Res.Commun.. 278・2. 333-337 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] S.Aoki et al.: "Identity of dimeric dihydrodiol dehydrogenase as NADP^+-dependent D-xylose dehydrogenase in pig liver"Chemico-Biol.Interact.. (2001)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] E.Arimitsu et al.: "Cloning and sequencing of the cDNA species for mammalian dihydrodiol dehydrogenases"Biochem.J.. 342-3. 721-728 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Y.Asada et al.: "Roles of His-79 and Tyr-180 of D-xylose/dihydrodiol Dehydrogenase in catalytic function"Biochem.Biophys.Res.Commun.. 278-2. 333-337 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] S.Aoki et al.: "Identity of dimeric dihydrodiol dehydrogenase as NADP^+-dependent D-xylose dehydrogenase in pig liver"Chemico-Biol.Interact.. (in the press). (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Y.Asada et al.: "Roles of His-79 and Tyr-180 of D-xylose/dehydrodiol dehydrogenase in catalytic function."Biochem.Biophys.Res.Commun.. 278・2. 333-337 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] S.Aoki et al.: "Identity of dimeric dihydrodiol dehydrogenase as NADP^+-dependent D-xylose dehydrogenase in pig liver"Chemico-Biol.Interact.. (印刷中). (2001)

    • Related Report
      2000 Annual Research Report
  • [Publications] E.Arimitsu et. al.: "Cloning and sequencing of the cDNA species for mammalian dihydrodiol dehydrogenases"Biochem.J.. 342・3. 721-728 (1999)

    • Related Report
      1999 Annual Research Report

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Published: 1999-04-01   Modified: 2016-04-21  

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